Lumefantrine

Usage

• Lumefantrine is an antimalarial drug used in combination with artemether for the treatment of acute, uncomplicated Plasmodium falciparum malaria. It is effective against the asexual blood stages of P. falciparum, but not against the gametocytes or hepatic stages. It is also not effective against other Plasmodium species like P. vivax, P. malariae, or P. ovale, but some patients in clinical studies had co-infection with P. falciparum and P. vivax.

• Pharmacological Classification: Antimalarial, specifically an aryl amino alcohol.

• Mechanism of Action: While the exact mechanism is not fully elucidated, lumefantrine is thought to interfere with heme polymerization within the malaria parasite’s food vacuole. This inhibits the formation of hemozoin, a non-toxic form of heme, leading to a buildup of toxic free heme, which damages the parasite.

Alternate Names

• Co-artemether (when used in combination with artemether).
• Brand Names: Coartem®

How It Works

• Pharmacodynamics: Lumefantrine exerts its antimalarial activity by disrupting heme detoxification within the Plasmodium falciparum parasite. This accumulation of heme results in parasite death.

• Pharmacokinetics:

  • Absorption: Oral absorption is enhanced when taken with fatty foods.
  • Metabolism: Primarily metabolized in the liver by CYP3A4.
  • Elimination: Primarily eliminated via feces with a long elimination half-life (4-6 days), some renal excretion.

• Mode of Action: Inhibits heme polymerase within the P. falciparum food vacuole which in consequence prevents hemozoin formation, leading to toxic heme accumulation and parasite death.

• Elimination Pathways: Hepatic metabolism via CYP3A4 followed by fecal excretion and to a lesser extent renal excretion.

Dosage

Standard Dosage

Lumefantrine is administered in fixed combination with artemether. The following dosages are for the artemether-lumefantrine combination based on 20mg/120mg tablets and 80mg/480mg tablets.

Adults (≥35 kg or >12 years):

20mg/120mg: Initial dose of four tablets, followed by four tablets at 8 hours, then four tablets twice daily (morning and evening) for 2 days (total 24 tablets). 80mg/480mg: Initial dose of one tablet, followed by one tablet at 8 hours, then one tablet twice daily for 2 days (total 6 tablets).

Children:

• 5 kg to <15 kg: Initial dose of one 20mg/120mg tablet, followed by one tablet at 8 hours, then one tablet twice daily for 2 days (total 6 tablets).
• 15 kg to <25 kg: Initial dose of two 20mg/120mg tablets, followed by two tablets at 8 hours, then two tablets twice daily for 2 days (total 12 tablets).
• 25 kg to <35 kg: Initial dose of three 20mg/120mg tablets, followed by three tablets at 8 hours, then three tablets twice daily for 2 days (total 18 tablets).

Pediatric safety considerations: Safety and efficacy in infants less than 5 kg have not been fully established.

Special Cases:

• Elderly Patients: No dosage adjustment necessary.
• Patients with Renal Impairment: Caution is advised in severe renal impairment.
• Patients with Hepatic Dysfunction: Caution is advised in severe hepatic impairment.

Clinical Use Cases

Lumefantrine-artemether is specifically indicated for uncomplicated malaria and is not indicated for severe malaria, prophylaxis, or use in clinical settings like intubation, surgical procedures, mechanical ventilation, or the ICU.

Side Effects

Common Side Effects:

Headache, dizziness, weakness, muscle or joint pain, fatigue, insomnia, vomiting, anorexia, fever, chills, cough, abdominal pain.

Rare but Serious Side Effects:

Cardiac arrhythmias (including QT prolongation), anaphylaxis, severe skin reactions.

Adverse Drug Reactions (ADR): QT prolongation and cardiac events.

Contraindications

• Hypersensitivity to artemether, lumefantrine, or any component of the formulation.
• Severe malaria.
• History of or family history of congenital QT prolongation or sudden cardiac death.
• Conditions known to prolong the QT interval.
• Concomitant use with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, St. John’s wort) or drugs known to prolong the QT interval.

Drug Interactions

• Drugs that prolong the QT interval (e.g., antiarrhythmics, antipsychotics, some antibiotics).
• CYP3A4 inducers (decrease lumefantrine levels).
• CYP2D6 inhibitors (may increase lumefantrine levels).
• Mefloquine (reduces lumefantrine absorption).
• Halofantrine (should not be administered within one month of halofantrine).
• Grapefruit juice (increases artemether exposure).
• Hormonal contraceptives (efficacy may be reduced).
• Antiretroviral medications (interactions with efavirenz, nevirapine, ritonavir/lopinavir).

Pregnancy and Breastfeeding

• Pregnancy: Recommended by WHO for uncomplicated P. falciparum malaria during all trimesters of pregnancy when the benefits outweigh the risks. Animal studies have shown some evidence of embryotoxicity.
• Breastfeeding: Use is considered acceptable in mothers nursing infants weighing at least 5 kg. Safety in infants weighing less than 5 kg is not established. Due to lumefantrine’s long half-life, breastfeeding interruption for one week after the last dose is recommended.

Drug Profile Summary

• Mechanism of Action: Inhibits heme polymerization in P. falciparum.
• Side Effects: Headache, dizziness, gastrointestinal disturbances, QT prolongation.
• Contraindications: Hypersensitivity, severe malaria, QT prolongation risk factors, concurrent use of contraindicated drugs.
• Drug Interactions: CYP3A4 inducers/inhibitors, QT prolonging drugs.
• Pregnancy & Breastfeeding: Generally safe, but caution advised; WHO recommends for use in pregnancy when benefit outweighs risk. Safe for breastfeeding for infants >5kg after one week following treatment cessation.
• Dosage: See detailed section above.

Popular Combinations

• Artemether and lumefantrine are always given as a fixed-dose combination.

Precautions

• Ensure adequate food intake for optimal absorption.
• Monitor for cardiac effects (QT prolongation).
• Use with caution in patients with renal or hepatic impairment.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Lumefantrine?

A: Lumefantrine is always co-administered with artemether. Dosage is weight-based and differs for adults and children (see detailed dosage section).

Q2: Can Lumefantrine be used in pregnancy?

A: Yes, the WHO recommends artemether-lumefantrine for uncomplicated malaria in all trimesters of pregnancy when the benefit outweighs potential risks.

Q3: What are the most common side effects of Lumefantrine?

A: Common side effects include headache, dizziness, nausea, vomiting, and anorexia.

Q4: What are the serious side effects of Lumefantrine?

A: QT prolongation and subsequent cardiac events, though rare, are the most serious side effects and warrant careful monitoring.

Q5: What are the contraindications for using Lumefantrine?

A: Contraindications include hypersensitivity, severe malaria, history of QT prolongation or conditions that predispose to QT prolongation, concomitant use of strong CYP3A4 inducers, and use with other drugs known to prolong QT interval.

Q6: How does Lumefantrine interact with other medications?

A: Lumefantrine interacts with drugs that affect CYP3A4 and CYP2D6 enzymes, those that prolong the QT interval, and some antimalarials like mefloquine. It can also reduce the efficacy of hormonal contraceptives. Review the drug interactions section for a detailed list.

Q7: Can Lumefantrine be used in breastfeeding mothers?

A: Yes, it is considered acceptable for infants greater than 5 kg. However, it is recommended that breastfeeding should not resume until at least one week after the last dose due to the long elimination half-life of lumefantrine.

Q8: How should Lumefantrine be administered?

A: Lumefantrine should be administered orally with food or a milky drink to enhance absorption.

Q9: What should be done if a patient vomits after taking Lumefantrine?

A: If vomiting occurs within one hour, the dose should be repeated. If vomiting continues, consider an alternative antimalarial treatment.

Q10: Is Lumefantrine effective against all types of malaria?

A: No, Lumefantrine, in combination with artemether, is primarily indicated for uncomplicated P. falciparum malaria. It is not effective against other Plasmodium species.